Predictors of Abdominal Aortic Aneurysm Sac Enlargement After Endovascular RepairClinical Perspective
Background—The majority of infrarenal abdominal aortic aneurysm (AAA) repairs in the United States are performed with endovascular methods. Baseline aortoiliac arterial anatomic characteristics are fundamental criteria for appropriate patient selection for endovascular aortic repair (EVAR) and key determinants of long-term success. We evaluated compliance with anatomic guidelines for EVAR and the relationship between baseline aortoiliac arterial anatomy and post-EVAR AAA sac enlargement.
Methods and Results—Patients with pre-EVAR and at least 1 post-EVAR computed tomography scan were identified from the M2S, Inc. imaging database (1999 to 2008). Preoperative baseline aortoiliac anatomic characteristics were reviewed for each patient. Data relating to the specific AAA endovascular device implanted were not available. Therefore, morphological measurements were compared with the most liberal and the most conservative published anatomic guidelines as stated in each manufacturer's instructions for use. The primary study outcome was post-EVAR AAA sac enlargement (>5-mm diameter increase). In 10 228 patients undergoing EVAR, 59% had a maximum AAA diameter below the 55-mm threshold at which intervention is recommended over surveillance. Only 42% of patients had anatomy that met the most conservative definition of device instructions for use; 69% met the most liberal definition of device instructions for use. The 5-year post-EVAR rate of AAA sac enlargement was 41%. Independent predictors of AAA sac enlargement included endoleak, age ≥80 years, aortic neck diameter ≥28 mm, aortic neck angle >60°, and common iliac artery diameter >20 mm.
Conclusion—In this multicenter observational study, compliance with EVAR device guidelines was low and post-EVAR aneurysm sac enlargement was high, raising concern for long-term risk of aneurysm rupture.
The elective management of abdominal aortic aneurysms (AAAs) has traditionally depended on open surgical aneurysm repair.1,2 However, recent developments in catheter-based endovascular techniques have led to a substantial increase in the proportion of AAAs managed electively with endovascular aortic aneurysm repair (EVAR). In 2006, 21 725 EVAR procedures were performed in the United States, exceeding for the first time the number of open surgical AAA repairs.3
Editorial see p 2782
Clinical Perspective on p 2855
The regulatory approval of EVAR devices in the United States requires manufacturers to measure technical factors such as fixation strength, sealing ability, and delivery accuracy in the laboratory. On the basis of these preclinical engineering assessments and clinical study results, specific anatomic characteristics (including aortic neck diameter, aortic neck length, aortic neck angle, and iliac artery morphology) are recommended to guide patient selection for EVAR. These instructions for use (IFU) are published and packaged with each device used in the United States.
Clinical trials for regulatory approval and postmarketing analyses, as well as randomized, controlled trials that compared EVAR with open AAA repair, have evaluated various clinical outcomes in patients meeting the specific anatomic requirements defined in the IFU.4–8 Several studies using national databases have also reported on clinical outcomes after EVAR; however, these studies lacked access to aortic and iliac artery anatomic data and therefore were unable to assess whether devices were used in accordance with published IFU or whether adherence to IFU affected clinical outcomes.3,9 Thus, the proportion of patients and the outcomes of patients who undergo EVAR with anatomy outside the device IFU are largely undocumented with respect to both short- and long-term complications, with the exception of a small number of single-center reports.10–12
These issues are of paramount importance when considering the long-term results of 2 randomized trials comparing EVAR and open AAA repair.13,14 These studies have demonstrated substantially lower morbidity and mortality after EVAR than after open repair. However, late follow-up of these cohorts has demonstrated that the early survival advantage of patients undergoing EVAR disappears with time, and a significant proportion of late deaths after EVAR are due to aneurysm rupture.13,14 The cause of aortic rupture after EVAR relates to repressurization of the aneurysm sac as a result of device failure or progression of native disease in the regions used to fixate and seal the device. Although the exact mechanism was not determined for each case of aortic rupture after endovascular repair in the EVAR study, these events were found to be closely linked with aortic aneurysm sac enlargement.15 Because aortic rupture has been shown to be an important cause of late death in highly selected patient populations within clinical trials, it is reasonable to hypothesize that commercial use of EVAR devices in patients who did not meet device IFU could result in a greater risk of aortic rupture.
The purpose of the present study was to use data from a large, multicenter cohort to determine the degree of compliance with IFU anatomic guidelines for EVAR, to examine changes in compliance with the IFU over the last decade, and to determine the relationship between baseline aortic and iliac artery anatomic characteristics and incidence of aortic aneurysm sac enlargement after EVAR.
Patients undergoing EVAR between January 1, 1999, and December 31, 2008, were assembled from a medical imaging repository at M2S, Inc. (West Lebanon, NH). Using standardized algorithms, M2S creates 3-dimensional computer models from computed tomography (CT) images of aortic aneurysms. In addition to serving as the core imaging laboratory for several large aneurysm management trials,16–18 M2S also provides these services to both private and academic hospitals throughout the world. For the purposes of this study, M2S provided deidentified data on all patients in its prospectively acquired database who underwent a CT scan before EVAR and had at least 1 CT scan after EVAR between 1999 and 2008 in the United States. M2S did not play any role in the study design, analysis, or interpretation of the data provided.
From the M2S database, patients were selected for inclusion in the present analysis according to the following criteria: clinical diagnosis of AAA with an aortic diameter >30 mm, preoperative CT scan demonstrating the absence of an infrarenal endovascular stent graft within the AAA (confirming the EVAR had not yet occurred), and at least 1 postoperative CT scan demonstrating the presence of a stent graft within the AAA (confirming that EVAR had occurred).
In an effort to further restrict our analyses to patients treated for an AAA (and to exclude patients treated primarily for an isolated iliac artery aneurysm), the required minimum aortic diameter was increased to 40 mm if either iliac artery diameter exceeded 20 mm. Patients were also excluded if they underwent EVAR in the context of premarketing or postmarketing studies in which M2S served as the core imaging laboratory.
Data Elements and Image Analysis
All patient, physician, and hospital identifiers were removed by M2S before the investigators received the data set. Available demographic variables included patient age, sex, and the US state in which the imaging studies were obtained. The exact date on which the CT scan was obtained was available for every patient for every CT scan. All other data elements were anatomic in nature and were obtained after CT scans underwent 3-dimensional processing and standardized measurements by M2S personnel. Measurements were performed by trained individuals blinded to patient, center, and operator through the use of validated techniques; all measurements obtained were consistent with the Society for Vascular Surgery Reporting Standards.19 All diameter measurements were calculated orthogonal to the vessel of interest (ie, in a plane at a right angle to the centerline of the lumen). All length and angle measurements were made along the lumen centerline.
Key anatomic measurements included maximum AAA sac diameter, aortic diameter at the lowest renal artery, aortic diameter at 15 mm below the lowest renal artery, aortic neck length (distance between the lowest renal artery and the origin of the aneurysm, indicated by a 10% increase in diameter), aortic neck angulation (angle calculated between the lowest renal artery, the origin of the aneurysm, and the aortic bifurcation), conical neck (aortic diameter 15 mm below the lowest renal artery ≥10% larger than the aortic diameter at the lowest renal artery), AAA volume, maximum common iliac artery diameter, minimum external iliac artery diameter, and length from the lowest renal artery to the aortic bifurcation.
It is important to note that M2S does not collect data relating to which specific AAA endovascular device was used and that this level of detail could not be discerned from the CT images. In addition, there were no data available detailing whether patients underwent any secondary reinterventions.
Compliance With Instructions for Use
The IFU for each approved endovascular device was reviewed with respect to year of device approval (Figure 1 and Table 1). For the purposes of this study, these criteria were incorporated into 3 descriptive variables called conservative IFU (most restrictive), liberal IFU (least restrictive), and time-dependent IFU (reflecting the most liberal IFU at each time point during the study period) (Table 2). As mentioned, the specific AAA endovascular device used was not contained in the data set, so graft-specific deviations from IFU for each specific patient could not be assessed.
End points were assessed at the time of each post-EVAR CT scan. The primary study end point, AAA sac enlargement, was defined as a growth of ≥5 mm in the AAA maximal diameter from pre-EVAR to any post-EVAR CT scan (based on Society for Vascular Surgery Reporting Standards19). The secondary study end point, endoleak, was assessed via a single-phase arterial contrast CT scan, and was defined as the presence of contrast-opacified blood within the aneurysm sac and outside the endovascular stent graft.
All anatomic measurements were analyzed in SAS (version 9.2, SAS Institute, Inc., Cary, NC). Variations over time in baseline demographic and anatomic characteristics were calculated with the Cochran-Armitage test for trend. For time-trend analyses, patients undergoing EVAR between 1999 and 2003 were grouped together to represent the early experience with EVAR (first 5 years of commercial device availability). Analysis of time-to-event occurrence of AAA sac enlargement was performed with the Kaplan-Meier method, and group differences (stratified by compliance with IFU) were compared by use of the log-rank test. For these survival analyses, all observations were censored at the time of the patient's last CT scan. To identify independent predictors of aortic aneurysm sac enlargement, all demographic and anatomic variables that were statistically significant on univariate analysis (P<0.05) were then introduced into a multivariable Cox proportional hazards model with backward selection. In addition to baseline characteristics, we evaluated the presence of an endoleak during follow-up as a potential predictor of AAA sac enlargement. This study was approved by the Institutional Review Board at the University of Massachusetts Medical School.
The study population consisted of 10 228 patients in the United States who underwent EVAR for AAA repair between 1999 and 2008. This cohort did not include the 216 patients (2.1%) who were identified as having isolated iliac artery aneurysms without a concurrent AAA, and were therefore excluded. The patients were primarily men (84.1%), had an average age of 73.9 years, and represented all regions of the United States (Table 3).
Baseline Anatomic Characteristics
All patients had a baseline CT scan before EVAR and at least 1 follow-up CT scan after EVAR; in total, 31 013 CT scans were reviewed. The average preoperative AAA maximum diameter was 54.8 mm; 6075 patients (59%) had an AAA maximum diameter <55 mm (Table 3). The average AAA neck diameter was 23.1 mm, with a mean length of 20.7 mm and a mean angle of 36.9°. In addition to the presence of an AAA, 1215 patients (11.9%) were found to have at least 1 common iliac artery aneurysm (>20-mm diameter). When all EVAR-treated patients were classified according to IFU criteria, 5983 patients (58.5%) were outside compliance with the conservative IFU, 3178 patients (31.1%) patients were outside the liberal IFU, and 4507 patients (44.1%) were outside the time-dependent IFU.
Demographic and Anatomic Trends Over Time
An increasing proportion of patients undergoing EVAR were ≥80 years of age over the decade-long period under study (Table 4). The maximum AAA diameter before EVAR did not change significantly over time, yet the average diameter of the AAA neck increased significantly over time. A greater proportion of patients undergoing EVAR had conical aortic necks as time progressed (30.0% in 1999 to 2003 versus 35.7% in 2008; P<0.001). Similarly, in more recent years, a larger proportion of patients undergoing EVAR had highly angulated aortic necks (7.0% in 1999 to 2003 versus 9.5% in 2008; P=0.004). The external iliac artery diameter decreased over the study period; 14.8% of patients in 1999 to 2003 had both external iliac arteries <6 mm compared with 17.5% in 2008 (P=0.05). Notably, no significant differences were observed in the proportion of patients treated outside either the conservative or liberal IFU throughout the study period.
Aortic Aneurysm Sac Enlargement
The mean duration of follow-up was 31±18 months, with an average of 3.03±0.93 postoperative CT scans available per patient. In the entire cohort, the proportions of patients who developed AAA sac enlargement at 1, 3, and 5 years after EVAR were 3%, 17%, and 41%, respectively. Importantly, 30% of patients who eventually manifested AAA sac enlargement did not demonstrate this enlargement until >3 years after EVAR. The rate of AAA sac enlargement was significantly higher in patients who underwent EVAR outside the IFU, regardless of whether lack of compliance was to conservative IFU, liberal IFU, or time-dependent IFU (Figure 2). In addition, when the cohort was stratified by year of endograft implantation (before 2004 versus after), the rate of AAA sac enlargement was significantly greater in the group undergoing EVAR more recently (2004 to 2008) than in those who underwent EVAR between 1999 and 2003 (Figure 2).
The presence of any endoleak during follow-up was documented in 3279 patients, for an overall incidence of 32%. The majority of endoleaks (76%) became evident during the first year of post-EVAR imaging. Of the 3279 patients who developed an endoleak, 692 (21.1%) were found, at some point on post-EVAR imaging, to develop aortic aneurysm sac enlargement.
Determinants of Aortic Aneurysm Sac Enlargement
On univariate analysis, the following patient characteristics were associated with an increased risk for AAA sac enlargement: age ≥80 years; conical aortic neck; aortic neck diameter ≥28 mm; aortic neck angle >60°; common iliac artery diameter >20 mm; anatomy outside conservative, liberal, or time-dependent IFU specifications; and presence of an endoleak during follow-up. On multivariable analysis (Table 5), the primary determinant of AAA sac enlargement was the presence of an endoleak on any postoperative CT scan (hazard ratio, 2.70; 95% confidence interval, 2.40 to 3.04). Additional significant predictors of AAA sac enlargement on multivariable analysis were patient age ≥80 years, aortic neck diameter ≥28 mm, neck angle >60°, and common iliac artery diameter >20 mm.
This study demonstrates that, in a large population of patients who underwent EVAR with commercial devices in the United States over a recent 10-year period, the incidence of AAA sac enlargement after EVAR was 41% at 5 years, a rate that increased over the study period. Liberalization of the anatomic characteristics deemed suitable for EVAR has occurred, and several of these factors, including aortic neck diameter, aortic neck angle, and common iliac artery diameter, were independently associated with aortic aneurysm sac enlargement. These observations raise the question of whether such liberalization is justified with current device designs. It is also interesting to note that 60% of the AAAs in this study were smaller than the 55-mm recommended threshold for elective repair established by data from randomized controlled trials.1,2
Endovascular stent-graft implantation requires proximal aortic neck anatomy and distal iliac artery anatomy that interact with the device in such a way that all blood flow is excluded from entering the aneurysm in an effort to eliminate pressurization of the aneurysm wall. These anatomic factors include vessel diameter, length, and angulation, among other factors. However, there is no agreement as to the specific minimal aortoiliac anatomic characteristics required to achieve durable endovascular repair. As a result, the IFU-specified anatomic characteristics changed over the study period. Because of these changes, we analyzed the preoperative anatomy in the context of the most conservative IFU, most liberal IFU, and time-dependent IFU.
In the absence of any information about the incidence of clinical complications or repeat interventions, we examined as our primary end point, AAA sac enlargement, because it provides the most direct evidence of EVAR failure to reduce the risk of rupture. This study end point has been used in other published reports,20,21 and has been associated with an increased risk of adverse outcomes, including the need for subsequent open repair and aneurysm rupture.22,23 The natural history of untreated aneurysms is to enlarge over time until eventual rupture. Endovascular repair aims to prevent aortic rupture; thus, AAA sac enlargement represents treatment failure, because it leaves the patient at risk of death resulting from rupture.
One possible exception to this rule relates to a subset of patients treated with the first-generation Gore Excluder device, which was marketed commercially from 2002 to 2003. This device was made of a higher-porosity graft material, and the post-EVAR AAA sac enlargement associated with this device has been suggested to carry a more benign prognosis, at least through intermediate-term follow-up.24 To assess whether this specific high-porosity device was an important factor contributing to the high rate of AAA sac enlargement seen in this study, we evaluated the patient groups before and after the first generation of this device was altered (2004). Surprisingly, the rate of AAA sac enlargement increased from 2004 to 2008 (Figure 2), suggesting that the use of this specific device did not explain our observed trends during the years under study. More likely, the liberalization of the anatomic characteristics deemed suitable for EVAR observed over the study period (ie, increased aortic neck diameter, increased proportion of patients with conical aortic necks, increased proportion of patients with highly angulated aortic necks) explains this trend. An alternative explanation for this trend may be that patients treated before 2004 were at higher medical risk, and that these procedures therefore carried a higher associated mortality. If so, more patients treated before 2004 may have died before manifesting AAA sac enlargement.
When analyzing the dates of the CT scans included in this study, we identified 1221 patients (11.9%) in this cohort who did not have any post-EVAR CT scans beyond 90 days from the date of the pre-EVAR CT scan. In these patients, it is possible that an insufficient amount of time elapsed for them to manifest AAA sac enlargement. As a result, the rate of AAA sac enlargement reported in this study may represent an underestimate.
The present study is the largest investigation to date using detailed pre-EVAR and post-EVAR anatomic CT imaging data to assess determinants of AAA sac enlargement after EVAR. However, several limitations are inherent in the analysis of this data set. All CT-, patient-, and hospital-related data were de-identified, so that there was no knowledge by the investigators about the enrolling clinicians, centers, or implanted devices. As a result, additional clinical data, including occurrences of secondary interventions, cannot be ascertained for patients included in this study. If a large number of the enlarging aneurysms were easily treated with a repeat intervention, the clinical implications of this end point would, to some extent, be mitigated. In addition, nonconsecutive submission of patient data by hospitals may have introduced an important selection bias. It is possible that hospitals may have submitted only their most complicated cases to M2S, such as those requiring secondary interventions or those with more challenging anatomy, but we are unable to assess this potential concern with the available data. However, one would hypothesize that if the impetus to obtain more detailed imaging information were driven by anatomic complexity, the aneurysms would be larger. This is clearly not the case, given that the majority of aneurysms in this study were actually smaller than the current treatment recommendations for treatment of AAA. To better understand the potential impact of these biases, we compared the characteristics of the 8596 patients in the M2S data set during the second half of our study period (2004 to 2008) with those of the 103 237 Medicare patients undergoing EVAR from 2004 to 2008 (approximating an 8% sample). The average age (74 years versus 76 years) and proportion of men (84% versus 83%) in the M2S and Medicare data sets were similar.9 These findings suggest that results from the M2S database are generalizable to a significant proportion of patients undergoing EVAR in the United States.
An additional potential limitation of this study relates to the fact that the exact date on which the EVAR procedure was performed is not known. As a result, it is impossible to know how much time elapsed between the pre-EVAR baseline CT scan and the date of the EVAR procedure. If enough time did elapse between the pre-EVAR baseline CT scan and the EVAR procedure, it is conceivable that the AAA sac enlargement observed may have occurred before the AAA repair. However, given that the average rate of AAA growth has been demonstrated to be only 3.2 mm/y,1 and that most surgeons proceed with repair well before 1 or 2 years has elapsed since obtaining the relevant imaging study, we do not believe that this mechanism plays a significant role in the findings observed.
In this study, we used the standard definition of maximum diameter growth ≥5 mm for AAA sac enlargement. We acknowledge that recent reports have suggested that changes in AAA sac volume may provide a more sensitive way in which to detect AAA sac growth.24–26 Future studies may help shed more light on which metric for detecting AAA sac growth is the most clinically useful.
In this multicenter patient population, compliance with published EVAR device IFU guidelines was low, and post-EVAR aneurysm sac enlargement was high, raising concern for long-term risk of aneurysm rupture. The anatomic determinants of AAA sac enlargement identified in this study clearly demonstrate the importance of patient selection when deciding to proceed with EVAR. The liberalization in anatomic criteria deemed appropriate for EVAR, observed throughout the study period, was associated with worse outcomes. A prospective EVAR registry that incorporates an independent imaging registry is necessary to define more precisely the specific aortic and iliac artery anatomic characteristics suitable for EVAR with currently available commercial devices. An improved understanding of these anatomic characteristics will ultimately improve the effectiveness and durability of EVAR to protect patients against AAA rupture.
Sources of Funding
This work was supported by the William Rogers Family Foundation. The funding agency had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Dr Greenberg receives research support from an intellectual property license and grant support from Cook Medical. The remaining authors have no conflicts to disclose.
Guest editor for this article was Gilbert Upchurch, Jr.
- Received December 16, 2010.
- Accepted March 17, 2011.
- © 2011 American Heart Association, Inc.
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Two recently published randomized trials comparing the effectiveness of open surgical and endovascular repair (EVAR) for the treatment of abdominal aortic aneurysms have demonstrated a significantly lower mortality rate for patients undergoing EVAR. However, the initial short-term survival advantage for patients undergoing EVAR was lost after long-term follow-up. A significant proportion of the late deaths of patients undergoing EVAR were due to aneurysm rupture. These concerning findings raise questions about the effectiveness and durability of EVAR to prevent death caused by abdominal aortic aneurysm rupture. This study uses a large multicenter cohort of patients who underwent endovascular abdominal aortic aneurysm repair in the United States. This data set is the largest EVAR cohort assembled to date that contains standardized, validated computed tomography anatomic measurements performed on all patients before and after EVAR. We demonstrate that compliance with published EVAR device guidelines is low, and that the incidence of aneurysm sac enlargement after EVAR is high. These unexpected findings raise significant concerns about the long-term risk of aneurysm rupture in patients undergoing EVAR in the United States. Furthermore, over the decade of study, liberalization of the anatomic characteristics deemed suitable for EVAR by device manufacturers has occurred, and several of these liberalized anatomic characteristics independently predict aortic aneurysm sac enlargement.